Complement-mediated hemolytic anemia is a significant health problem, and contributes to numerous disorders of the red blood cells, such as paroxysmal nocturnal hemoglobinuria (PNH). PNH is a hematological disorder characterized by the clonal expansion of one or a few hematopoietic stem cells which are incapable of glycosylphosphatidylinositol (GPI)-anchor biosynthesis, due to an acquired somatic mutation in the phosphatidylinositol glycan class A (PIG-A) gene. Affected progeny cells are deficient in all GPI-anchored surface proteins, including complement regulators CD55 and CD59. Thus, PNH red blood cells (RBCs) are vulnerable to activated complement, and particularly to the membrane attack complex (MAC), resulting in chronic intravascular hemolysis with recurrent exacerbations. Other complement-mediated disorders that affect red blood cells include atypical hemolytic uremic syndrome (aHUS); chronic hemolytic anemia; antibody-mediated autoimmune hemolytic anemia; anemia caused by hemoglobinopathies such as sickle cell disease; anemia caused by infection such as malaria; anemia due to transfusion reaction; and cold agglutinin disease (CAD).
Treatment with eculizumab, a monoclonal antibody (Mab) directed against complement component 5 (C5), has been partially effective in PNH and other hematological disorders. However, a significant subpopulation of patients with PNH exhibit suboptimal hematological response to treatment with anti-C5 Mab. In this subpopulation, little improvement of anemia is observed, and some still require blood transfusion, with continuing signs of persistent hemolysis (reticulocytosis, elevated unconjugated bilirubin). Risitano and Rotoli, Biologics, 2:205-222 (2008). The recurrence may be characterized as “breakthroughs” where hemolytic activity may persist despite treatment with terminal complement inhibitors. Hill et al., Blood, 106:2559-65 (2005). For these subjects, a need remains for additional methods and materials for the effective treatment of PNH.
Complement inhibitors are known in the art, and a new class of targeted complement inhibitors has been developed, which allows treatment in a fashion which results in high localized concentrations of inhibitor at the tissue sites where complement is activated, while minimizing potentially adverse systemic effects. This class of inhibitors includes, for example, TT30 (SEQ ID NO:3), TT31 and TT32. TT30 is an immunomodulatory compound which inhibits the complement alternative pathway. TT30 comprises a complement alternative pathway inhibitory portion of Factor H protein, which is targeted to sites of complement activation and inflammation through fusion with a portion of the complement receptor 2 protein (CR2 or CD21) which is known to bind to tissue/cell-fixed fragments of the complement component 3 (C3). TT31 is similar to TT30, but contains an additional copy of the complement alternative pathway inhibitory portion of Factor H protein. TT32 comprises a complement inhibitory portion of complement receptor 1 (CR1), targeted through fusion with the same portion of the CR2 protein. CR1 is known to be a broader inhibitor of complement than is Factor H. TT32 will therefore inhibit not only the complement alternative pathway, but will locally inhibit both the classic and lectin pathways of complement as well. Suitable targeted inhibitors are described in Gilkeson et al., US Patent Publication 2008/0221011, the disclosure of which is hereby specifically incorporated herein by reference.